2-hydroxy-1 4-naphthoquinone aminobenzoates

ABSTRACT

2-HYDROXY-1,4-NAPHTHOHYDROQUINONE AMINOBENZOATES, PREPARED BY CATALYTICALLY HYDROGENATING THE CONDENSATION PRODUCT OF A 2-HYDROXY-1,4-NAPHTHOQUINONE AND A NITROBENZOYL HALIDE, ARE USEFUL AS ANTIHAEMORRHAGIC AND CAPILLARY PROTECTIVE AGENTS.

United States Patent M Int. c1. 00% 79/46, 101/62 US. Cl. 260-396 R 14Claims ABSTRACT OF THE DISCLOSURE 2 hydroxy 1,4 naphthohydroquinoneaminobenzoates, prepared by catalytically hydrogenating the condensationproduct of a Z-hydroxy-1,4-naphthoquinone and a nitrobenzoyl halide, areuseful as antihaemorrhagic and capillary protective agents.

RELATED APPLICATION This application is a continuation-in-part ofapplication Ser. No. 493,245 filed Oct. 5, 1965 now abandoned.

SUMMARY The present invention is directed to antihaemorrhagic andcapillary protective agents of the formula E 0 NHg g m- Q,

R is either hydrogen or lower alkyl, e.g. methyl, ethyl,

propyl, isopropyl and butyl; and

each of R and R" is, independently, either hydrogen; lower alkyl, e.g.methyl, ethyl, propyl, isopropyl and butyl; or lower alkoxy, e.g.methoxy, ethoxy, propoxy and butoxy;

(I) wherein to a process for the preparation of said agents and tointermediates formed in the preparation of said agents.

The preferred compounds of this invention are those wherein each of Rand R" is hydrogen and R is either hydrogen or methyl. When R" is otherthan hydrogen, it is preferably in the 6- or 7-position. The amino groupis preferably in the para-position.

It is an object of the subject invention to provide therapeuticallyactive compounds having low acute and subacute toxicity. A furtherobject is to produce compounds having a marked antihaemorrhagic activityand which can be administered orally. Another object is to obtaincompounds which provide a capillary protective action. An additionalobject is to synthesize compounds having the noted properties. Stillfurther objects will be apparent from the description and examples.

UTILITY The compounds of this invention (esters I) have such a lowtoxicity that no deaths resulted from administering per os up to 2.0grams/kilogram of body weight to mice, rats and rabbits. Said compoundsproduce a marked antihaemorrhagic activity in dosages of as little as0.2 mg./kg. and retain such action when administered in doses up to '0mg./kg. or higher. The consequent utility as antihaemorrhagic agents isconfirmed by standard pharmacological tests in rabbits and mice.

Patented Feb. 1, 1972 Compounds I are also useful as capillaryprotective agents. For this purpose they are administered, e.g., orallyin doses of from 0.2 to 20 mg./kg. The capillary protective action hasbeen confirmed by standard tests on albino rabbits.

Compounds I are administered to mammals orally in standard dosage forms,e.g. tablets and capsules. The average daily dose varies, but isordinarily Within the range of from 0.2 to 50 milligrams (mg.) perkilogram (kg) of body weight. It may be administered either as a singledose or in divided doses at regular intervals from two to four times perday.

Each of the compounds of this invention may be, e.g., incorporated, fororal administration, in a tablet as the sole active ingredient. Atypical tablet is constituted by from 1 to 3 percent binder, e.g.tragacanth; from 3 to 10 percent disintegrating agent, e.g. corn starch;from 2 to 10 percent lubricant, e.g. talcum; from 0.25 to 1.0 percentlubricant, e.g. magnesium stearate; an average dosage of activeingredient; and q.s. 100 percent of filler, e.g. lactose; allpercentages being by weight. Tablets are prepared according to standardtabletting techniques, which are well-known in the art, employing thenecessary amounts of conventional granulating liquids, e.g. alcoholSD-30 and purified water. An exemplary tabletting formulation is:

Alcohol SD-3 0, purified water, q.s.

DETAILS Esters I are prepared by reacting a 2-hydroxy-1,4-naphthoquinoneof the formula with a nitrobenzoyl halide of the formula zN E X X Q(III) wherein X is halo, e.g. :bromo and iodo, but preferably chloro;

in an inert solvent, e.g. benzene, chloroform and tetrahydrofuran, andin contact with a tertiary amine, e.g. pyridine, triethylamine anddimethylaniline. (In Formulae II and III and, in the absence of acontrary indication, throughout the disclosure, each of R, R and R hasits aboveascribed definition.) The resulting corresponding nitrobenzoicesters of the formula are obtained in yields ranging from to percent,based on the weight of the starting materials.

Compounds II and HI are either known compounds or are prepared accordingto published procedures from available starting materials. ExemplaryCompounds II include:

2-ethyl-4-nitrobenzoyl chloride, 2-nitro-4-propylbenzoyl chloride,

2-isopropyl-S-nitrobenzoyl chloride,

3-butyl-4-nitrobenzoyl chloride, 5-methoxy-2-nitrobenzoyl chloride,2-ethoxy-3-nitrobenzoyl chloride and 3-methoxy-4-nitrobenzoyl bromide.

The nitrobenzoic acid esters IV are catalytically reduced with hydrogenin an inert solvent, e.g. dioxane and tetrahydrofuran, at a pressure offrom 1 to atmospheres and at a temperature of from 20 to 60 C. Thecatalyst employed for the catalytic reduction is a finely divided metalcatalyst, e.g. platinum, palladium and nickel, which is in intimatecontact with said nitrobenzoic acid esters during the reduction.

The naphthoquinonic system is thus first reduced to the correspondingnaphthohydroquinonic system with the absorption of one mole of hydrogenper mole of ester, yielding the corresponding 2(nitrobenzoyloxy)-1,4-dihydroxy-naphthalene. On continuation of thereduction, a further three moles of hydrogen, per mole of ester, areabsorbed, corresponding to the reduction of the nitro group to primaryamino, to produce the corresponding Compound I with yields in the orderof from 70 to 80 percent.

PREFERRED EMBODIMENTS The following examples are merely illustrative.Reactions wherein R, R, R" and X have any particular meaning or aredesignated as in a specified position are exemplary of correspondingreactions and the preparation of corresponding intermediates and finalproducts wherein said R, R, R" and X have any other meaning within thescope contemplated by this invention.

Example I In a 1 litre flask fitted with a cooler having a calciumchloride closure, a solution of 50 grams (g.) of dry 2-,

hydroxy-3-methyl-1,4-naphthoquinone, 55 g. of p-nitro-- benzoyl chlorideand 30 g. of pyridine (dried by distilling over NaOH) in 300 milliliters(ml.) of benzene (dried over sodium) is refluxed for one hour. Aftercooling, the

. precipitate is collected by suction filtering and washed formed at 84g. of 2 hydroxy 3-mcthyl-L4-naphtho 4 quinone p-nitrobenzoate; yellowcrystals; melting point (M.P.) 178-182 C. The product is re-crystallizedby solution in boiling chloroform, followed by dilution in ethanol,melting then at 180182 C.

A solution of 50 g. of 2-hydroxy-3-methyl-1,4-naphthoquinonep-nitrobenzoate in 500 ml. of pure dioxane is admixed with 0.5 g. ofplatinum dioxide and stirred in the presence of hydrogen under normalpressure and at the temperature of 50 C., measuring the gas absorption.Absorption is stopped after 13 litres of gas have been absorbed, whichtakes 3-4 hours. The catalyst is removed by filtering, and the filtrateis diluted with 2 litres of petroleum ether (M.P. 40-70 C.). An oilylayer is separated; the supernatant liquid is decanted and the residuetaken up in 200 ml. of benzene, heating a few minutes to boiling. Aftercooling, the precipitate is collected by suction filtering and washedwith 100 ml. of benzene, thus obtaining2-hydroxy-3-methyl-1,4-naphthohydroquinone 2 (p aminobenzoate)[2-(p-aminobenzoyloxy) -3.-methyl 1,4 naphthohydroquinone] containing amolecule of crystal dioxane, which is removed by vacuum drying at 80 C.The residue is a greyish white powder melting with decomposition between214 and 218 C. Said residue can be re-crystallized from an acetone andcyclohexane mixture.

Replacing the 2-hydroxy-3-methyl-1,4-naphthoquinone with an equivalentof either 3-ethyl-2-hydroxy-1,4-naphthoquinone, 2-hydroxy-3-propyl-1,4-naphthoquinone, 2-hydroxy-3-isopropyl-1,4-naphthoquinone or2-hydroxy-3-(n-octyl)-1,4-naphthoquinone results in the preparation, insimilar manner, of

respectively.

Stopping the catalytic hydrogenation after the absorption of one mole ofhydrogen (per mole of naphthoquinone-p-nitrobenzoate) yields theintermediate, 3- methyl-Z- (p-nitrobenzoyloxy) -1,4-naphthohydroquinone.

'Example II A solution of 10 g. of 2-hydroxy-1,4-naphthoquinone, 12 g.of p-nitrobenzoyl chloride and 8 ml. of pyridine in 100 ml. of benzeneis refluxed for 45 minutes. The same procedure used in Example I issuccessively repeated and, after treatment with water, 16.2 g. ofZ-hydroxynaphthoquinone p-nitro-benzoate as yellow prisms are recovered;the same, re-crystallized from chloroform, melt at 190-192 C.

10 g. of this product in 100 ml. of dioxane are hydrogena-ted in thepresence of 0.1 g. of platinum dioxide under the pressure of 5atmospheres and at the temperature of 40 C. After the absorption of fourmolar equivalents of hydrogen is completed, the product is filtered andthe filtrate evaporated in a rotating evaporator under a pres-- sure of15 millimeters (mm.) of mercury. The residue is taken up in 50 ml. ofbenzene and vacuum dried at 60 C. 8.5 g. ofZ-hydroxy-l,4-naphthohydroquinone-2-(paminobenzoate) as a light pinkpowder are recovered; M.P. 200202 C. with decomposition.

Replacing the p-nitrobenzoyl chloride with an equivalent of either2-methyl-4-nitrdbenzoylchloride, 3-methoxy-4- nitrobenzoyl chloride,3-ethyl-4-nitrobenzoyl chloride or 3- ethoxy-S-nitrobenzoyl chlorideresults in the preparation,

in similar manner, of 2-(2'-methyl-4'-nitrobenzoyloxy)- 1,4naphthohydroquinone, 2 (3-meth0xy-4'-nitrobenzoyloxy) 1,4naphthohydroquinone, 2 (3' ethyl-4'- nitrobenzoyloxy) 1,4mph-thohydroquinone Q Z-( ethoxy--nitrobenzoyloxy)-1,4-naphthohydroquinone, respectively.

Example HI A solution of 30 g. of 2-hydroxy-3-methyl-1,4-naphthoquinone,35 g. of m-nitrobenzoyl chloride and 20 m1. of anhydrous pyridine in 250ml. of dry tetrahydrofuran is refluxed for 30 minutes. The solution ishot filtered to remove the insoluble pyridinium chloride. The filtrateis dry distilled over a water bath, and the residue is taken up in 100ml. of ethanol by boiling for minutes. After cooling, a yellowcrystalline precipitate of 2-hydroxy-3-methyl-1,4-naphthoquinone-m-nitrobenzoate, M.P. 167 -169 C., is formed andcollected. A 10 g. solution of this compound in 200 ml. of pure and drytetrahydrofuran is hydrogenated in the presence of 1 g. of palladium on10% carbon at normal temperature C.) and pressure (1 atmosphere). Whenhydrogen absorption stops (after about two hours), the product isfiltered and the filtrate evaporated to dryness at reduced pressure in anitrogen stream. Residue is taken up in 100 ml. of benzene, collected byfiltering and vacuum dried at 70 C., thus obtaining as a White powder, 2hydroxy 3 methyl-1,4- naphthohydroquinone-Z-(m-aminobenzoate), M.P. 174-178 C. with decomposition.

Replacing the 2-hydroxy-3-methyl-1,4-naphthoquin0ne with an equivalentof either 2-hydroxy-3,5-, 3,6- 3,7- or 3,8-dimethyl-1,4-naphthoquinone,2-hydroxy-6-rnethoxy- 3-methyl-1,4-naphth0quinone or7-ethoxy-2-hydroxy-1,4- naphthoquinone results in the preparation, insimilar manner, of 2-(m-aminobenzoyloxy)-3,5-, 3,6-, 3,7-, or3,8-dimethyl 1,4 naphthohydroquinone, Z-(m-aminobenzoyloxy)6-methoxy-3-methyl-l,4-naphthohydroquinone or 2- (m aminobenzoyloxy) 7ethoxy 1,4 naphthohydroquinone, respectively.

Example IV From 10 g. of 2-hydroxy-1,4-naphthoquinone, 12 g. ofm-nitrobenzoyl chloride and 8 ml. of anhydrous pyridine there areobtained, according to the procedure described in Example I,Z-hydroxy-naphthoquinonem-nitrobenzoate as yellow crystals, M.P. l87189C. Reduction of this product is carried out as described in Example II,but using 200 ml. of dioxane and 0.2 g. of platinum dioxide for 10 g. ofnitro-ester; 2-hydroxy-1,4-naphthohydroquinone-2-(m-amindbenzoate), M.P.2l42l6 C. with decomposition, is thus obtained.

Example V From 10 g. of 2-hydroxy-3-methyl-l,4-naphthoquinone, 11 g. ofo-nitrobenzoyl chloride, 6 g. of pyridine and 100 ml. of benzene,operating according to Example I, 2- hydroxy 3methyl-1,4-naphthoquinone-o-nitrobenzoate, M.P. l78180 C., is obtained.10 g. of this product in 100 ml. of dioxane are reduced as described inExample I, providing 2 hydroxy-3-methyl-1,4-naphthohydroquinone-2-(o-aminobenzoate), M.P. l68l72 C. with decomposition.

Each of the final products prepared according to this invention isuseful as an antihaemorrhagic agent, the final products prepared as perthe specific examples are merely exemplary. The correspondingnitrobenzoates and naphthoquinones are useful as intermediates in thepreparation of said final products.

What is claimed is:

1. A compound of the formula x R" z wherein Z is a member selected fromthe group consisting of (a) COC(Y) =C(R)CO and (b) C(OH)1=C(Y)C(R)=C(0H)Y is a member selected from the group consisting of (c) and (d) Y being(d) only when Z is (b);

R is a member selected from the group consisting of hydrogen and loweralkyl; and

each of R and 'R" is, independently, a member selected from the groupconsisting of hydrogen, lower alkyl and lower alkoxy. 2. A compoundaccording to claim 1 of the formula 3. A compound according to claim 1of the formula H N03 HQ n i R,

4. A compound according to claim 1 of the formula 5. A compoundaccording to claim 4 wherein each of R and R" is hydrogen.

6. A compound according to claim 5 wherein R is hydrogen.

7. The compound according to claim 6 which is 2-hydroxy-1,4-naphthohydroquinone-Z-(p-aminobenzoate 8. The compoundaccording to claim 6 which is 2-hydroxy-l ,4-naphthohydroquinone-Z-(m-aminobenzoate) 9. A compound according to' claim 5 wherein R ismethyl.

10. The compound according to claim 9 which is 2-(pamindbenzoyloxy3-methyl- 1,4-naphthohydroquinone 11. The compound according to claim 9which is 2- hydroxy 3 methyl 1,4 naphthohydroquinone-Z-(maminobenzoate12. The compound according to claim 9 which is 2- hydroxy 3 methyl 1,4naphthohydroquinone-Z-(oaminobenzo ate) 13. A process for preparingcompounds as defined in claim 1, which comprises:

(a) reacting a compound of the formula wherein X is halo, with ahydroxynaphthoquinone of the formula IL Y in an inert solvent and in thepresence of a tertiary amine to obtain the corresponding nitrobenzoateand (b) subjecting the obtained nitrobenzoate to catalytic hydrogenationin an inert solvent at a pressure of from 1 to 10 atmospheres and at atemperature of from 20 to 60 C., in the presence of a finely dividedmetal hydrogenation catalyst, the period of hydrogenation being soregulated as to produce the 1,2,4- trihydroxynaphthalene 2(nitrobenzoate) upon the absorption of one mole of hydrogen per mole ofester, or the corresponding 2 (aminobenzoate) after absorption of fourmole of hydrogen per mole of ester. 14. A process according to claim 13wherein X is chloro.

References Cited Fieser, L. F. et al.: Organic Chemistry (1956), 3rd Ed.Pub. by Reinhold Publishing Corp. New York, pp. 18l- 182 and 596 reliedon; QD 257 F5 (1956).

LORRAINE A. WEINBERGER, Primary Examiner L. A. THAXTON, AssistantExaminer US. Cl. X.'R.

